EP0454580A2 - Nouveaux derivés de nojirimycine - Google Patents

Nouveaux derivés de nojirimycine Download PDF

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Publication number
EP0454580A2
EP0454580A2 EP91401096A EP91401096A EP0454580A2 EP 0454580 A2 EP0454580 A2 EP 0454580A2 EP 91401096 A EP91401096 A EP 91401096A EP 91401096 A EP91401096 A EP 91401096A EP 0454580 A2 EP0454580 A2 EP 0454580A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
mmol
mixture
glucitol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP91401096A
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German (de)
English (en)
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EP0454580A3 (en
EP0454580B1 (fr
Inventor
Brigitte Lesur
Jean-Bernard Ducep
Charles Danzin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharmaceuticals Inc
Original Assignee
Merrell Dow Pharmaceuticals Inc
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Filing date
Publication date
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Publication of EP0454580A2 publication Critical patent/EP0454580A2/fr
Publication of EP0454580A3 publication Critical patent/EP0454580A3/en
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Publication of EP0454580B1 publication Critical patent/EP0454580B1/fr
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Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • This invention relates to novel N-derivatives of 1-deoxy nojirimycin, to the method for their preparation and to their use in the treatment of diabetes and their use against retro-viruses, particularly in the treatment of acquired immuno-deficiency syndrome (AIDS).
  • AIDS acquired immuno-deficiency syndrome
  • Q is a divalent moiety bridging the 1-deoxy-nojirimycin with the silicon atom to which Q is attached. In all instances the moieties of Q are directly attached to the nitrogen atom of the 1-deoxy nojirimycin.
  • the C1 ⁇ 7 alkylene moiety includes the straight, branched and cyclized manifestations of saturated lower aliphatic hydrocarbons including such alkylene moieties derived from alkyl radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, pentyl, hexyl, cyclohexyl, cyclohexylmethyl, preferably n-butyl, n-propyl, methyl or ethyl, (yielding, of course such moieties as for example (-CH2-), (-CH2-CH2-), (-CH2CH2CH2-), (-CH2-(C6H10) ⁇ wherein the silicon is preferably attached at the meta-position of the cyclohexyl moiety, and the like).
  • alkyl radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
  • the (CH2) m cyclopentenylene and cyclohexenylene moieties have their unsaturation at the carbon atom to which the silicon is attached
  • p is 1 or 2 and the -SiR1R2R3 moiety is attached to the phenyl moiety at its 3-position.
  • Preferred (CH2) p T moieties are illustrated as
  • R1 is C1 ⁇ 7 alkyl or C1 ⁇ 7 alkoxy
  • methyl, ethyl, methoxy and ethoxy are preferred.
  • hydroxy C1 ⁇ 6 alkyl hydroxymethyl is preferred.
  • R1 is polyhydroxy C1 ⁇ 6 alkyl it is preferred that there be 1, 2 or 3 OH radicals, each one of which is attached to a different carbon atom of the C1 ⁇ 6 alkyl moiety and in such instances it is preferred that the hydroxy be located on carbon atoms other than the carbon atom attached directly onto the silicon atom; the same concepts also be true for the mono- and polyalkoxy substituted C1 ⁇ 6 alkyl moieties in which case methoxy is preferred.
  • the (CH2) p X,Y-substituted phenyl moieties are those wherein both X and Y are H, or one is H and the other is OH, chloro, methyl or methoxy or both are OH, Cl, methyl or methoxy.
  • the Q radical contains a (CH2) m moiety it is preferred that m be 1 or 2, and when Q contains (CH2) n moieties n preferably is zero or 1.
  • the of Formula I will also be referred to as -SiR1R2R3 and -Q-Si-R1R2R3, respectively.
  • the trans- isomers are preferred over the cis- isomers.
  • the pharmaceutically acceptable salts of the compounds of formula I include salts formed with non-toxic organic or inorganic acids such as, for example, from the following acids: hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic acid, acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnamic, palmitic, itaconic and benzenesulfonic and the like.
  • non-toxic organic or inorganic acids such as, for example, from the following acids: hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic acid, acetic, propionic, tartaric, citric, lactic, malic, mandelic
  • the compounds of this invention are prepared by chemical reactions and procedures which are analogously known in the art and the selection of a particular route to any specific compound is governed by principles well known and appreciated by those of ordinary skill in the art.
  • the compounds of this invention may be prepared according to the reaction scheme outlined below.
  • Q-SiR1R2R3 is as previously defined, R is H or Bz, Bz is benzyl, a preferred hydroxy-protecting group, X′ is halogeno, mesylate or tosylate.
  • Reaction Scheme A The synthesis of Reaction Scheme A is initiated by the condensation of an optionally hydroxy-protected 1-deoxy nojirimycin with an excess quantity ( ⁇ three times) of the appropriate X′-Q-SiR1R2R3 reactant in the presence of an excess of triethylamine (NEt3) in dimethyl formamide (DMF).
  • X′ is the iodide.
  • the so-produced compounds (3) are purified, preferably using chromatographic techniques and are then deprotected according to standard procedures well known in the art.
  • deprotection is effected by using transfer hydrogenation with formic acid in methanol with Pd/C or by catalytic hydrogenation, preferably using palladium on carbon in an appropriate solvent, e.g. ethanol.
  • the deprotected products (4) are in the form of quaternary salts with the HCOO ⁇ anion and thus must be neutralized; the neutralization preferably being effected using an ion exchange resin such as Dowex AX-8.
  • Q represents a bridging moiety containing an unsaturation (e.g., allylic, allenic, acetylenic, cyclopentenylene, cyclohexenylene or the unsaturated (CH2) p T moieties) it is preferred that the 2-, 3- and 6-position hydroxy groups not be protected in view of the difficulties encountered when removing the benzyl protecting groups unless special procedures are employed (e.g., when Q contains such unsaturated moieties a process using sodium in ammonia is preferred).
  • an unsaturation e.g., allylic, allenic, acetylenic, cyclopentenylene, cyclohexenylene or the unsaturated (CH2) p T moieties
  • 1-Deoxy nojirimycin may be obtained by reducing nojirimycin (5-amino-5-deoxy-D-glucopyranose) using the method of Tetrahedron Letters, 24 , 2125-2144, 1968, as referenced in European Patent Application 89 112284.8 published on January 10, 1990, with publication No. 0350012.
  • the preparation of 1-deoxy nojirimycin and its hydroxy-protected analogs (2) are also disclosed in the specific examples disclosed herein.
  • the X′-Q-SiR1R2R3 reactant are either known compounds or may be prepared by methods analogously known in the art.
  • Methanesulfonylchloride (0.73 ml, 9 mmol) was added dropwise to a solution of 3-(trimethylsilyl)-1-propanol (1.2 ml, 7.56 mmol) cooled at 0°C in 20 ml of dichloro-methane. After 45 minutes stirring, the reaction mixture was partitioned between water and dichloromethane, the organic phase was separated, the solvent was evaporated under reduced pressure to afford the expected 3-(trimethylsilyl)-1-propanol, methanesulfonate in crude quantitative yield.
  • Benzyl(bromomethyl)dimethylsilane [Colm, Earborn and Foad M.S., Malmond J. Organomet. Chem., 209 , 13 (1981)] (12 g, 0.05 mmol) and sodium iodide (45 g, 0.3 mmol) are refluxed with stirring in acetone (500 ml) during 24 hours.
  • the reaction mixture is cooled, filtered and the solvent is evaporated under reduced pressure.
  • the residue is dissolved in ether and washed with water.
  • the organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl(iodomethyl)dimethylsilane (13.7 g, 95%) as a slightly yellow oil.
  • n-Bu4N+I ⁇ (76 mg, 0.20 mmol) was added followed by benzyl bromide (3.30 ml, 27.5 mmol) added dropwise. The mixture was stirred overnight at room temperature. After hydrolysis with saturated aqueous ammonium chloride tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with water and extracted three times with ether. The organic phase was dried over sodium sulfate. Filtration and evaporation under reduced pressure afforded an oil.
  • Methyl 5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-glucofuranoside (10.8 g, 22.2 mmol) was dissolved at room temperature in tetrahydrofuran (20 ml). The solution was cooled at -10°C and trifluoroacetic acid (120 ml) was added dropwise followed by addition of water (20 ml). The mixture was stirred at 0°C during 24 h. The mixture was evaporated under reduced pressure without heating. The residue was taken with ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • 1,5-Dideoxy-1,5- ⁇ [4-(trimethylsilyl)-2-butynyl]imino ⁇ -D-glucitol (0.1 g, 0.35 mmol) is dissolved in methanol (5 ml) and lindlar catalyst (25 mg) is added. The mixture is hydrogenated at atmospheric pressure overnight. The catalyst is filtered off and the solvent is evaporated under reduced pressure to afford 1,5-dideoxy-1,5- ⁇ [4-(trimethylsilyl)-2(Z)-butenyl]imino ⁇ -D-glucitol as an amorphous solid (0.09 g, 90%).
  • the resin is removed by filtration, water is removed by lyophilization and the expected product 1,5-dideoxy-1,5- ⁇ [(trimethylsilyl)-methyl]imino ⁇ -D-glucitol is obtained as an amorphous solid (0.016 g, 45%).
  • the resin is removed by filtration, water is removed by lyophilization and the expected product 1,5-dideoxy-1,5- ⁇ [(trimethylsilyl)-propyl]imino ⁇ -D-glucitol is obtained as an amorphous solid (0.17 g, 85%).
  • the resin is removed by filtration, water is removed by lyophilization and the expected product 1,5-dideoxy-1,5- ⁇ [4-(trimethylsilyl)butyl]imino ⁇ -D-glucitol is obtained as an amorphous solid (0.02 g, 75%).
  • 2,3,6-Tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (0.2 g, 0.46 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (10 ml) under an inert atmosphere and palladium 10% on charcoal (0.4 g) is added. The mixture is stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved in methanol and the solution is filtered through a membrane (Millex-SR 0.5 ⁇ M). Evaporation of solvent gives a sticky solid which is further triturated in ethanol to give the expected 1,5-dideoxy-1,5-imino-D-glucitol as a beige powder (60 mg, 80%).
  • Solvents are evaporated under reduced pressure and the residue is flash chromatographed on a silica gel column, eluted with dichloromethane:ethanol 9:1 to 7:3 to give 0.1 g (40%) of the expected 1,5-dideoxy-1,5- ⁇ [3-(trimethylsilyl)-phenyl]methyl ⁇ imino -D-glucitol as a white powder.
  • Step B 1,5-Dideoxy-1,5- ⁇ [3-(trimethylsilyl)propyl]imino ⁇ -D-glucitol
  • the mixture was cooled to 5°C (ice-water bath), filtered, and the filter cake was washed with ice-water (2 x 3 ml) and air-dried for 1 hour to give 0.64 g of a white solid.
  • the solid was dissolved in hot (80°C) water (12 ml) and cooled to give 0.56 g (66%) of the desired product as white plates.
  • Enzymes which catalyze the hydrolysis of complex carbohydrates e.g. ⁇ -glycosidases, convert non-absorbable carbohydrates into absorbable sugars.
  • the rapid action of these enzymes, particularly following the intake of high levels of carbohydrates lead to acute high levels in blood glucose which, in the case diabetics, lead to undesirable manifestations, thus it has been a long-sought goal to find compounds which will obviate the hyperglycemia caused by dietary improprieties.
  • Dietary improprieties means eating habits associated with overeating, overdrinking, and failure to maintain a balanced diet such as the excessive intake of carbohydrates, which metabolize to glucose and which lead to obesity.
  • the compound of the present invention are administered to subjects in need of such therapy, e.g., mammals such as humans.
  • the compounds of this invention (I) are potent and long-lasting inhibitors of ⁇ -glucosidase and, by standard laboratory methods for determining serum glucose levels, are shown to be useful for the treatment of disease states caused by the underutilization and/or overproduction of serum glucose without adversely affecting the rate of transport across cell membranes.
  • the compounds are useful in the treatment of diabetes and obesity.
  • an effective amount of a compound of this invention is that amount required to reduce the amount of serum glucose (relative to a control) following the ingestion of carbohydrates convertible to absorbable glucose.
  • the specific dosage for the treatment of any specific patient suffering from either disease state will depend upon such factors as size, type and age of the patient as well as the patients' dietary habits and the severity of the disease state, all of which are factors normally familiar to and considered by the attending diagnostician treating the patient.
  • the compounds are to be administered orally at a dose of 0.01 to 2 milligrams per kilogram of body weight (MPK) with a dose of 0.025 to 0.5 MPK being preferred.
  • MPK milligrams per kilogram of body weight
  • the compounds preferably are to be administered orally at mealtimes in single or multiple unit doses containing 1 mg to 10 mg.
  • the term includes the practice of treating the disease as well as continued administration of dose regimens suitable for the maintenance of the desired weight for the patient.
  • the compounds of the instant invention (I) will exert an inhibitory effect on glycosidase enzymes that are essential for elaboration of the final structure of the oligosaccharide side-chains of glycoproteins, particularly the HIV (gp 120) glycoprotein.
  • Suitable assay techniques e.g. syncytial formation, the reverse transcriptase assay, immunofluorescence tests and election microscopy, may be used to evaluate the effects on HIV viral growth and for determining dose regimens. Anti-viral effects may be confirmed by immunofluorescence with serum for virally infected patients.
  • the compounds of this invention may be administered by parenteral means; specific doses being within the above stated dose range for treatment of diabetes and obesity.
  • the compounds of this invention may also be effectively utilized in conjunctive therapy with compounds known to be useful in treating patients with AIDS such as for example 2,3-dideoxycytidine, 2,3-dideoxyadenine, interferon, interleukin-2 and the like.
  • the compounds are preferably incorporated in a pharmaceutical formulation comprising a pharmaceutical carrier in admixture with a compound of this invention.
  • pharmaceutical carrier refers to known pharmaceutical excipients useful in formulating pharmaceutically active compounds for internal administration to animals, and which are substantially non-toxic and non-sensitizing under conditions of use.
  • the compositions can be prepared by known techniques for the preparation of tablets, capsules, elixirs, syrups emulsions, dispersions and wettable and effervescent powders, and can contain suitable excipients known to be useful in the preparation of the particular type of composition desired. Suitable pharmaceutical carriers and formulation techniques are found in standard texts, such as Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.
  • Preferred R1 moieties are C1 ⁇ 7 alkyl, phenyl or a hydroxylated alkyl
  • preferred R2 and R3 moieties are C1 ⁇ 10 alkyl, phenyl or benzyl.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
EP91401096A 1990-04-27 1991-04-25 Nouveaux derivés de nojirimycine Expired - Lifetime EP0454580B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP90401169A EP0453692A1 (fr) 1990-04-27 1990-04-27 Nouveaux dérivés de nojirimycine
EP90401169 1990-04-27

Publications (3)

Publication Number Publication Date
EP0454580A2 true EP0454580A2 (fr) 1991-10-30
EP0454580A3 EP0454580A3 (en) 1992-04-29
EP0454580B1 EP0454580B1 (fr) 1995-12-27

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EP90401169A Withdrawn EP0453692A1 (fr) 1990-04-27 1990-04-27 Nouveaux dérivés de nojirimycine
EP91401096A Expired - Lifetime EP0454580B1 (fr) 1990-04-27 1991-04-25 Nouveaux derivés de nojirimycine

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Application Number Title Priority Date Filing Date
EP90401169A Withdrawn EP0453692A1 (fr) 1990-04-27 1990-04-27 Nouveaux dérivés de nojirimycine

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EP (2) EP0453692A1 (fr)
JP (1) JP2968088B2 (fr)
KR (1) KR100191051B1 (fr)
CN (1) CN1028368C (fr)
AR (1) AR248026A1 (fr)
AT (1) ATE132153T1 (fr)
AU (1) AU632926B2 (fr)
CA (1) CA2041331C (fr)
DE (1) DE69115750T2 (fr)
DK (1) DK0454580T3 (fr)
ES (1) ES2084126T3 (fr)
FI (1) FI97885C (fr)
GR (1) GR3018797T3 (fr)
HU (1) HU212496B (fr)
IE (1) IE72477B1 (fr)
IL (1) IL97975A (fr)
NO (1) NO179913C (fr)
PT (1) PT97485B (fr)
TW (1) TW201302B (fr)
ZA (1) ZA912994B (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5986230A (en) * 1996-09-13 1999-11-16 Uncle Ben's, Inc. Method and apparatus for sorting product

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0282168A2 (fr) * 1987-03-10 1988-09-14 Safe-Haul Limited Soupape pneumatique
EP0350012A2 (fr) * 1988-07-08 1990-01-10 Meiji Seika Kaisha Ltd. Composition antivirale

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1555654A (en) * 1977-06-25 1979-11-14 Exxon Research Engineering Co Agricultural burner apparatus
EP0282618A1 (fr) * 1987-03-18 1988-09-21 Vereniging Het Nederlands Kanker Instituut 1-déoxynojirimycine comme médicament thérapeutique anti-HIV
US5043273A (en) * 1989-08-17 1991-08-27 Monsanto Company Phosphorylated glycosidase inhibitor prodrugs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0282168A2 (fr) * 1987-03-10 1988-09-14 Safe-Haul Limited Soupape pneumatique
EP0350012A2 (fr) * 1988-07-08 1990-01-10 Meiji Seika Kaisha Ltd. Composition antivirale

Also Published As

Publication number Publication date
NO179913B (no) 1996-09-30
CA2041331C (fr) 2001-08-28
JPH0586072A (ja) 1993-04-06
KR910018390A (ko) 1991-11-30
JP2968088B2 (ja) 1999-10-25
AR248026A1 (es) 1995-05-31
IL97975A (en) 1996-05-14
NO911665D0 (no) 1991-04-26
GR3018797T3 (en) 1996-04-30
CN1028368C (zh) 1995-05-10
TW201302B (fr) 1993-03-01
FI912033A (fi) 1991-10-28
HU911430D0 (en) 1991-11-28
HU212496B (en) 1996-07-29
AU7535191A (en) 1991-11-07
ES2084126T3 (es) 1996-05-01
KR100191051B1 (ko) 1999-06-15
IE911417A1 (en) 1991-11-06
IE72477B1 (en) 1997-04-23
DK0454580T3 (da) 1996-01-29
EP0453692A1 (fr) 1991-10-30
CN1056104A (zh) 1991-11-13
FI912033A0 (fi) 1991-04-26
DE69115750D1 (de) 1996-02-08
FI97885C (fi) 1997-03-10
ATE132153T1 (de) 1996-01-15
NO911665L (no) 1991-10-28
HUT57782A (en) 1991-12-30
ZA912994B (en) 1992-01-29
FI97885B (fi) 1996-11-29
NO179913C (no) 1997-01-08
CA2041331A1 (fr) 1991-10-28
EP0454580A3 (en) 1992-04-29
AU632926B2 (en) 1993-01-14
PT97485B (pt) 1998-08-31
IL97975A0 (en) 1992-06-21
PT97485A (pt) 1992-01-31
DE69115750T2 (de) 1996-05-15
EP0454580B1 (fr) 1995-12-27

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